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Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.

Abstract

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

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  • Authors+Show Affiliations

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China.

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    Department of Genetics, Tianjin Medical University, Tianjin, 300070, China.

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    Department of Genetics, Tianjin Medical University, Tianjin, 300070, China.

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    Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA.

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    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy.

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    Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA.

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    Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: qf@medmail.com.cn.

    State Key Laboratory of Medicinal Chemical Biology, 2011 Collaborative Innovation Center for Biotherapy; Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, 300071, China. Electronic address: liulin@nankai.edu.cn.

    Source

    Translational oncology 12:9 2019 Jun 14 pg 1164-1176

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31207547

    Citation

    Gong, Peng, et al. "Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer." Translational Oncology, vol. 12, no. 9, 2019, pp. 1164-1176.
    Gong P, Wang H, Zhang J, et al. Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer. Transl Oncol. 2019;12(9):1164-1176.
    Gong, P., Wang, H., Zhang, J., Fu, Y., Zhu, Z., Wang, J., ... Liu, L. (2019). Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer. Translational Oncology, 12(9), pp. 1164-1176. doi:10.1016/j.tranon.2019.05.010.
    Gong P, et al. Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer. Transl Oncol. 2019 Jun 14;12(9):1164-1176. PubMed PMID: 31207547.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer. AU - Gong,Peng, AU - Wang,Hua, AU - Zhang,Jingsong, AU - Fu,Yudong, AU - Zhu,Zhengmao, AU - Wang,Jinmiao, AU - Yin,Yu, AU - Wang,Haiying, AU - Zhou,Zhongcheng, AU - Yang,Jiao, AU - Liu,Linlin, AU - Gou,Mo, AU - Zeng,Ming, AU - Yuan,Jinghua, AU - Wang,Feng, AU - Pan,Xinghua, AU - Xiang,Rong, AU - Weissman,Sherman M, AU - Qi,Feng, AU - Liu,Lin, Y1 - 2019/06/14/ PY - 2019/05/09/received PY - 2019/05/13/accepted PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez SP - 1164 EP - 1176 JF - Translational oncology JO - Transl Oncol VL - 12 IS - 9 N2 - Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs. SN - 1936-5233 UR - https://www.unboundmedicine.com/medline/citation/31207547/Telomere_Maintenance-Associated_PML_Is_a_Potential_Specific_Therapeutic_Target_of_Human_Colorectal_Cancer L2 - https://linkinghub.elsevier.com/retrieve/pii/S1936-5233(19)30202-5 DB - PRIME DP - Unbound Medicine ER -